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Deficiency in the Repair of DNA Damage by Homologous Recombination and Sensitivity to Poly(ADP-Ribose) Polymerase Inhibition

Nuala McCabe^1,2, Nicholas C. Turner², Christopher J. Lord², Katarzyna Kluzek³, Aneta Biakowska³, Sally Swift^1,2, Sabrina Giavara⁴, Mark J. O'Connor⁴, Andrew N. Tutt², Magorzata Z. Zdzienicka^3,5, Graeme C.M. Smith⁴ and Alan Ashworth^1,2

¹ Cancer Research UK Gene Function and Regulation Group and ² The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, United Kingdom; ³ Department of Molecular Cell Genetics, N. Copernicus University, Collegium Medicum in Bydgoszcz, Bydgoszcz, Poland; ⁴ KuDOS Pharmaceuticals Ltd., Cambridge, United Kingdom; and ⁵ Department of Toxicogenetics, Leiden University Medical Center, Leiden, the Netherlands

Requests for reprints: Alan Ashworth, The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, Fulham Road, London SW3 6JB, United Kingdom. Phone: 44-20-7153-5317; Fax: 44-20-7153-5340; E-mail: alan.ashworth{at}icr.ac.uk.

Deficiency in either of the breast cancer susceptibility proteins BRCA1 or BRCA2 induces profound cellular sensitivity to the inhibition of poly(ADP-ribose) polymerase (PARP) activity. We hypothesized that the critical role of BRCA1 and BRCA2 in the repair of double-strand breaks by homologous recombination (HR) was the underlying reason for this sensitivity. Here, we examine the effects of deficiency of several proteins involved in HR on sensitivity to PARP inhibition. We show that deficiency of RAD51, RAD54, DSS1, RPA1, NBS1, ATR, ATM, CHK1, CHK2, FANCD2, FANCA, or FANCC induces such sensitivity. This suggests that BRCA-deficient cells are, at least in part, sensitive to PARP inhibition because of HR deficiency. These results indicate that PARP inhibition might be a useful therapeutic strategy not only for the treatment of BRCA mutation-associated tumors but also for the treatment of a wider range of tumors bearing a variety of deficiencies in the HR pathway or displaying properties of ‘BRCAness.’ (Cancer Res 2006; 66(16): 8109-15)

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